The broad, long-term goal of the proposed studies is to provide a precise molecular basis of how particular biophysical signatures endowed to antibodies correlate to antibody-dependent cellular cytotoxicity (ADCC) induction, which appears to confer protection against HIV infection and inhibits disease progression. To do so, we will address two Specific Aims: (1) to determine the biophysical basis of interactions between antibodies and Fc receptors that lead to increased induction of ADCC in elite controller populations relative to individuals with chronic progressive disease; and (2) to determine the structural and energetic bases for how differential antibody glycosylation results in increased ADCC induction and HIV protection. We have recently produced experimental evidence showing: (i) that antibodies generated by HIV elite controllers bind to the Fc?RIIIa receptor with significantly higher affinity than antibodies generated by chronically infected individuals; (ii) that antibodies from chronically infected individuals bind with increasingly weaker affinity to Fc?RIIIa throughout the early stages of HIV infection; and (iii) that a panel of broadly neutralizing HIV antibodies exhibits widely varying affinities to Fc?RIIIa. Each of these results correlates to functional readouts of ADCC induction. Our findings indicate that there exists an entirely novel and previously unrecognized biophysical signature of antibodies produced during HIV infection that correlates to immunological protection. These data suggest a unique opportunity to develop novel HIV vaccine technologies that rationally harness ADCC function to control viral replication. We hypothesize that the ADCC-inducing properties of antibodies generated by elite controllers protect these individuals from disease progression and that recapitulation of the biophysical characteristics of these antibodies in at-risk individuals via novel vaccination strategies will confer broad protection against HIV infection.